1 

Grading of Recommendations, Assessment, Development, and Evaluation 

(GRADE): Recombinant zoster vaccine (RZV) and Herpes Zoster LiveAttenuated Vaccine (ZVL) 

Introduction 

Since 2008, ZOSTAVAX®, a one-dose of herpes zoster live-attenuated vaccine (ZVL), has been 

recommended by the Advisory Committee for Immunization Practices (ACIP) for the prevention of 

herpes zoster in immunocompetent adults aged 60 years and older [1-2].

On October 20th 2017, SHINGRIX, a two-dose, adjuvanted, recombinant zoster vaccine (RZV) was 

approved by the FDA for the prevention of herpes zoster in immunocompetent adults aged 50 years and 

older. From 2015-2017, the ACIP reviewed evidence and considerations regarding the use of RZV

(formerly referred to as herpes zoster subunit vaccine or HZ/su) in the United States to prevent herpes 

zoster and its complications. As part of ACIP’s process, a systematic review and Grading of 

Recommendations, Assessment, Development and Evaluation (GRADE) of the evidence for both herpes 

zoster vaccines was conducted and presented to ACIP. There were no conflicts of interest reported by 

CDC and ACIP Herpes Zoster Work Group members involved in the GRADE analysis. 

The GRADE approach was adopted by ACIP in 2010 as the framework for evaluating the scientific 

evidence that informs recommendations for vaccine use. GRADE was used to evaluate both RZV and 

ZVL. Evidence of benefits and harms were reviewed based on the GRADE approach [3].

Separate GRADE analyses were conducted for each vaccine.

• RZV: GRADE was used to evaluate routine vaccination of healthy older adults with the 

recombinant zoster vaccine. The primary policy question was “Should a two-dose series of the 

recombinant zoster vaccine be given routinely to immunocompetent adults aged 50 years and 

older for the prevention of herpes zoster?”

• ZVL: GRADE was used to evaluate routine vaccination of healthy older adults with the liveattenuated herpes zoster vaccine (ZVL). The primary policy question was “Is one dose of ZVL

safe and effective at preventing herpes zoster and postherpetic neuralgia PHN in the United 

States among immunocompetent adults aged 50 years and older?” 

Methods for GRADE 

GRADE of RZV studies 

We conducted a systematic review of evidence on the efficacy and safety of a two dose regimen of

recombinant zoster vaccine (RZV or SHINGRIX) to immunocompetent adults aged 50 years and older. 

We assessed outcomes and evaluated the quality of evidence using the GRADE approach. 

We identified studies in Medline, Embase, CINAHL, Cochrane, Scopus and clinicaltrials.gov, without any 

language or date restrictions. Search terms are described in Table 1. 

https://www.cdc.gov/vaccines/acip/recs/grade/herpes-zoster-h.pdf 1/22/2018
2 

Articles were included if they provided data on vaccination with RZV and 1) involved human subjects; 2) 

reported primary data; 3) included immunocompetent adults aged 50 years or older; 4) included data 

relevant to the outcomes being measured; and 5) included data for the dosage and timing being 

recommended (50 μg gE/AS01B, 2 doses at 0 and 2 months). Efforts were also made to obtain 

unpublished and other relevant data by hand-searching reference lists, and consulting with vaccine 

manufacturers and subject matter experts. Title and abstracts were screened independently by two 

separate reviewers. After title and abstract screening, 22 studies were identified for in-depth review. Of 

these, 6 were still ongoing or had not yet reported results; 3 studies were done among 

immunocompromised participants; and 3 included co-administration of RZV with another vaccine as the 

intervention. This left 10 studies for the GRADE analysis [4-13]. Characteristics of these studies are 

presented in Table 2. 

Beneficial and harmful outcomes for assessment were selected by the Work Group during work group 

calls and via online surveys where members were asked to rank the importance of relevant outcomes. 

The outcomes deemed critical by the work group were prevention of herpes zoster, prevention of PHN, 

and serious adverse events related to vaccination. Outcomes deemed important by the work group 

were duration of protection against herpes zoster and reactogenicity, specifically Grade 3 reactions

(reactions that prevent normal activities) following vaccination. 

The results of the GRADE analysis were presented to ACIP in February 2017.

Table 1. Evidence retrieval strategy, RZV 

Database Search terms

Medline

(OVID)

1946-

(herpes zoster and subunit) OR (HZ ADJ5 subunit) OR HZ su OR GSK 1437173A

Embase

(OVID)

1947-

(herpes zoster and subunit) OR (HZ ADJ5 subunit) OR HZ su OR GSK 1437173A

CINAHL

(Ebsco)

1982-

(herpes zoster and subunit) OR (HZ ADJ5 subunit) OR HZ su OR GSK 1437173A

Cochrane

Library

("herpes zoster" and subunit) OR (HZ NEAR/5 subunit) OR "HZ su" OR "GSK 1437173A"

Clinicaltrails.gov herpes zoster subunit OR HZ subunit OR RZV OR GSK 1437173A

Scopus TITLE-ABS-KEY(("herpes zoster" and subunit) OR (HZ NEAR/5 subunit) OR "HZ su" OR "GSK 

1437173A") AND NOT INDEX(medline)

Abbreviations: RZV: Recombinant zoster vaccine

Table 2. Characteristics of Included Studies, RZV 

Author, year Study design

(N=total enrolled)

Population VE [95% CI] Safety

Cunningham, 

2016

RCT, 18 countries 

(N=14,816)

Immunocompetent

adults ≥70 yrs

VE (HZ): 

89.8% [84.2-93.7]

VE (PHN): 

88.8% [68.7-97.1]

Serious adverse events (SAE)

Intervention: 0.2% [0.1-0.3]

Placebo: 0.1% [0.0-0.2]

Reactogenicity
3

VE (HZ), by year post 

vaccination:

1y: 97.6% [90.9-99.8]

2y: 92.0% [82.8-96.9]

3y: 84.7% [69.0-93.4]

4y: 87.9% [73.3-95.4]

Any Grade 3 symptoms: 

Intervention: 11.9% [9.2-15.0]

Placebo: 2.0% [1.0-3.6]

Lal, 2015 RCT, 18 countries

(N=16,160)

Immunocompetent

adults ≥50 yrs

VE (HZ): 

97.2% [93.7-99.0]

Serious adverse events

Intervention: 0.0% [0.0-0.1]

Placebo: 0.0% [0.0-0.1]

Reactogenicity

Any Grade 3 symptoms: 

Intervention: 15.6% [14.5-16.7]

Placebo: 1.9% [1.5-2.3]

Chlibek, 2013 RCT, 3 countries

(N=410)

Immunocompetent

adults ≥50 yrs

N/A Serious adverse events

No vaccine-related SAEs reported 

through month 14 

Reactogenicity

Any Grade 3 symptoms: 

Intervention: 9.3%

Placebo: 5.3% 

Chlibek, 2014

and Chilbek, 

2016+

RCT, 4 countries

(N=715)

Immunocompetent

adults ≥60 yrs

N/A Serious adverse events

No vaccine related SAEs through 

month 72

Reactogenicity:

Any Grade 3 symptoms: Not 

reported

Specific Grade 3 symptoms: 1.2%-

4.8% (myalgia most commonly 

reported symptom)

Lal, 2018+ RCT, 2 countries

(N=119)

Immunocompetent

adults ≥50 yrs

N/A Serious adverse events

No vaccine related SAEs through 

month 12

Reactogenicity

Any solicited Grade 3 symptoms:

Intervention: 15.1%

Leroux-Roels, 

2012+

RCT, Belgium

(N=135)

Immunocompetent

adults 50-70 yrs

N/A Serious adverse events

No vaccine related SAEs through 

month 42

Reactogenicity

Any Grade 3 symptoms: Not 

reported
4

Specific Grade 3 symptoms: 0%-20% 

(redness most commonly reported 

symptom)

Vink, 2017+ RCT, Japan

(N=60)

Immunocompetent

adults ≥50 yrs

N/A Serious adverse events

No vaccine related SAEs through 

month 12

Reactogenicity

Any Grade 3 symptoms: Not 

reported

Specific Grade 3 symptoms: 0%-5%

(redness most commonly reported 

symptom)

Godeaux, 

2017+

Non-RCT, 2 

countries

(N=96)

Immunocompetent

adults ≥50 yrs

N/A Serious adverse events

No vaccine related SAEs through 

month 12

Reactogenicity

Any Grade 3 symptoms: Not 

reported

Specific Grade 3 symptoms: 0%-10% 

(fatigue most commonly reported 

symptom)

Lal, 2013+ Non-RCT, 

Australia

(N=10)

Immunocompetent

adults 50-69 yrs

N/A Serious adverse events

No serious adverse events reported 

Reactogenicity

Any Grade 3 symptoms: 

Intervention: 40%

Abbreviations: RZV: Recombinant zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% Confidence 

Interval; HZ: herpes zoster; PHN: post-herpetic neuralgia; SAE: Serious adverse events; RCT: randomized controlled 

trial; Non-RCT: non-randomized clinical trial; 

+ No comparison group: no participants received no vaccine or placebo.

GRADE of ZVL studies 

We conducted a systematic review of evidence on the effectiveness and safety of a live attenuated 

herpes zoster vaccine (ZVL or ZOSTAVAX®) for immunocompetent adults aged 50 years and older. We 

assessed outcomes and evaluated the quality of evidence using the GRADE approach. 

We identified studies in Medline, Embase, CINAHL, Cochrane, Scopus and clinicaltrials.gov, without any 

language or date restrictions. Search terms are described in Table 3. 
5

Articles were included if they provided data on vaccination with one dose of ZVL and 1) involved human 

subjects; 2) reported primary data; 3) included immunocompetent adults aged 50 years or older; and 4) 

included data relevant to the outcomes being measured. Efforts were also made to obtain unpublished 

and other relevant data. Title and abstracts were screened independently by two separate reviewers. 

After title and abstract screening, 159 studies were identified for further review. Of these, 52 did not 

report outcomes of interest, 27 did not report data for ZVL, 23 had results reported in another study, 11 

were still ongoing or had not yet reported results; and 7 were individual case reports. This left 40 studies 

for the GRADE analysis [14-53]. Characteristics of these studies are presented in Table 4. 

The outcomes deemed critical by the work group were prevention of herpes zoster, prevention of PHN, 

and serious adverse events related to vaccination. Outcomes deemed important by the work group 

were duration of protection against herpes zoster (defined as 4 or more years post vaccination) and 

reactogenicity following vaccination. 

The results of the GRADE analysis were presented to ACIP in June 2017.

Table 3. Evidence retrieval strategy, ZVL 

Database Strategy

Medline

(OVID)

1946-

(zostavax OR (zoster AND (vaccine ADJ2 live*)) OR (zoster AND (attenuated ADJ2 live)) OR (zoster AND 

(vaccine ADJ2 attenuated)) OR ((zoster ADJ3 vaccin*) AND shingles))

Embase

(OVID)

1947-

(zostavax OR (zoster AND (vaccine ADJ2 live)) OR (zoster AND (attenuated ADJ2 live)) OR (zoster AND 

(vaccine ADJ2 attenuated)) OR ((zoster ADJ3 vaccin*) AND shingles))

CINAHL

(Ebsco)

1982-

(zostavax OR (zoster AND (vaccine N2 live*)) OR (zoster AND (attenuated N2 live)) OR (zoster AND 

(vaccine N2 attenuated)) OR ((zoster N3 vaccin*) AND shingles))

Cochrane

Library

(zostavax OR (zoster AND (vaccine NEAR/2 live*)) OR (zoster AND (attenuated NEAR/2 live)) OR (zoster 

AND (vaccine NEAR/2 attenuated)) OR ((zoster NEAR/3 vaccin*) AND shingles))

Clinicaltrails.gov Zostavax OR "zoster live vaccine" OR "zoster live attenuated" OR "zoster vaccine attenuated" 

Scopus TITLE-ABS-KEY(zostavax OR (zoster AND (vaccine W/2 live*)) OR (zoster AND (attenuated W/2 live)) OR 

(zoster AND (vaccine W/2 attenuated)) OR ((zoster NEAR/3 vaccin*) AND shingles)) AND NOT 

INDEX(medline)

Table 4. Characteristics of Included Studies, ZVL 

Author, year Study design

(N=total enrolled)

Population VE [95% CI] Safety 
6

Oxman, 2005

(SPS)

RCT, USA

(N=38,546)

Immunocompetent

adults ≥60y

VE (HZ): 

51.3% [44.2-57.6]

VE (PHN): 

66.5% [47.5-79.2]

Serious adverse events (SAE)

Intervention: 1.9%

Placebo: 1.3%, p<0.05*

Reactogenicity

Any injection-site symptoms: 

Intervention: 48%

Placebo: 17%, p<0.05

Schmader, 

2012 (STPS)

RCT w/limitations, 

USA

(N=14,270)

Immunocompetent

adults ≥60y

VE (HZ), by year post 

vaccination:

4y*: 44.6% [20.5-61.8]

5y*: 43.1% [5.1-66.5]

6y: 30.6% [-6.0-54.6]

*HZ events and person-years 

follow-up pooled for SPS and 

STPS

VE (PHN), 3 to 7 years 

post vaccination:

60% [-10-87%]

Serious adverse events 

No serious adverse events 

related to the vaccination 

reported. 

Morrison, 

2015 (LTPS)

RCT w/limitations, 

USA

(N=6,867)

Immunocompetent

adults ≥60y

VE (HZ), by year post 

vaccination:

7y*: 46.0% [28.4–60.2]

8y*: 31.1% [11.2–47.6]

9y: 6.8% [−16.5-26.4]

10y: 14.1% [−11.3-34.9]

11y: −1.7% [−57.1-37.9]

*HZ events and person-years 

follow-up pooled for STPS 

and LTPS

VE (PHN), 7 to 11 years 

post vaccination:

35% [9-56]

Serious adverse events 

No serious adverse events 

related to the vaccination 

reported. 

Schmader, 

2012 (ZEST)

RCT, North America 

and Europe

(N=22,439)

Immunocompetent

adults 50-59y

VE (HZ): 69.8% [54.1-

80.6]

Serious adverse events

Intervention: 0.6%

Placebo: 0.5%, p>0.05

Reactogenicity

Any injection-site symptoms: 

Intervention: 64%

Placebo: 14%, p<0.05

Langan, 2013 Cohort, USA

(N=766,330)

Medicare 

enrollees, 

adults ≥65y

VE (HZ): 48% [39-56]

VE (PHN): 59% [21-79]

Did not report safety results.
7

Tseng, 2014 Cohort, USA

(N=21,476)

KPSC members, 

adults ≥60y who 

later undergo 

chemotherapy 

Hazard ratio (HZ, 

vaccinated vs 

unvaccinated): 

0.58 [0.46-0.73]

Did not report safety results.

Tseng, 2016b Cohort, USA

(N=3,492)

KPSC members, 

adults ≥60y with 

end-state renal 

disease 

Hazard ratio (HZ, 

vaccinated vs 

unvaccinated): 

0.49 [0.29-0.85]

Did not report safety results.

Tseng, 2015 Cohort, USA

(N=2,310)

KPSC members, 

adults ≥60y

Risk ratio (PHN, 

vaccinated vs 

unvaccinated): 

0.59 [0.41-0.85]

Did not report safety results.

Baxter, 2017 Cohort, USA

(N=1.3 million)

KPNC members, 

adults ≥50y

VE (HZ): 49.1% [47.5-

50.6]

Did not report safety results.

Marin, 2015 Case control, USA

(N=628)

Adults aged ≥60y VE (HZ): 54.2% [32.0-

69.2]

VE (PHN): 55.2% [0.0-

91.6]

Did not report safety results.

Baxter, 

2016a

Cohort, USA

(N=1.3 million)

KPNC members,

adults ≥50y

VE (PHN) = 68.7% [64.6-

72.3]

Did not report safety results.

Tseng, 2016a Cohort, USA

(N=706,312)

KPSC members, 

adults ≥60y

VE (HZ), by year post 

vaccination:

• 1y: 68.7% [66.3-70.9]

• 2y: 49.5% [45.7-53.1]

• 3y: 39.1% [33.8-43.9]

• 4y: 35.2% [28.3-41.4]

• 5y: 37.1% [29.1-44.2]

• 6y: 32.9% [23.1-41.5]

• 7y: 16.5% [1.4-29.3]

• 8y: 4.2% [-24.0-25.9]

Did not report safety results.

Izurieta, 2017 Cohort, USA

(N=1,891,984)

Medicare 

enrollees, 

adults ≥65y

VE (HZ), by year post 

vaccination

• ≤3y: 33% [32-35]

• ≥4y: 19% [17-22]

Did not report safety results.

Murray, 2011 RCT, Canada, 

Germany, Spain, 

UK, US

(N=11,999)

Immunocompetent

adults ≥60y

Did not report VE. Estimated risk of SAEs within 

42 days was 1.41% for vaccine 

recipients versus 1.12% for 

placebo, with a relative-risk of 

1.26 [0.91-1.73]

MacIntyre, 

2010

RCT, Australia, 

Canada, Germany, 

Italy, Spain, UK

(N=475)

Immunocompetent

adults ≥60y

Did not report VE. Serious adverse events

No SAE related to vaccine 

reported within 28 days 

Reactogenicity

Any injection-site symptoms: 

Intervention: 36% 
8

Placebo: 11% 

Mills, 2010 RCT, USA

(N=101)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAE related to vaccine 

reported within 28 days 

Reactogenicity

Any injection-site symptoms: 

Intervention: 46% 

Placebo: 4% 

Beals, 2016 RCT, USA

(N=224)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAE related to vaccine 

reported within 42 days 

Reactogenicity

Any injection-site symptoms: 

Intervention: 52% 

Placebo: 13%

Hata, 2016 RCT, Japan

(N=62)

KPNC members,

adults ≥60y

Did not report VE. Serious adverse events

No SAE related to vaccine 

reported within 42 days 

Reactogenicity

Any injection-site symptoms: 

Intervention: 8% 

Placebo: 11%

Macaladad, 

2007

RCT, Brazil, Costa 

Rica, Colombia, 

Mexico, Peru, 

Venezuela, 

Phillipines

(N=21)

Immunocompetent

adults ≥30y

Did not report VE. Serious adverse events

No SAE related to vaccine 

reported within 42 days 

Reactogenicity

Any injection-site symptoms: 

Intervention: 11% 

Placebo: 0%

Zoran, 2016 RCT, USA

(N=28,785)

Immunocompetent

adults ≥60y

Did not report VE. Reactogenicity

Any Grade 3 symptoms: Not 

reported

Specific Grade 3 symptoms: 

0.4%-0.9% (erythema most 

commonly reported 

symptom)

Baxter, 2012 Cohort, USA

(N≈29,000)

KPNC members,

adults ≥60y

Did not report VE. Compared rates of adverse 

events in a 42-day risk time 

period immediately following 

vaccination with rates in the 

same cohort in a subsequent 

comparison time period. 

Found increased relative risks 
9

for coronary atherosclerosis 

and other heart disease, 

percutaneous transluminal 

coronary angioplasty, 

systemic lupus erythematosus 

and connective tissue 

disorders. But after medical 

chart review found no safety 

concerns within 42 days of 

vaccination.

Tseng, 2012 Cohort, USA

(N= 193,083)

Adults ≥50y Did not report VE. Compared rates of adverse 

events using a case-centered 

and self-controlled case series 

design and found no 

increased risk for 

cerebrovascular events; 

cardiovascular events; 

meningitis; encephalitis; and 

encephalopathy; and RamsayHunt syndrome and Bell's 

palsy. The risk of allergic 

reaction was significantly 

increased within 1-7 days of 

vaccination [relative risk = 

2.13, 95% confidence interval 

(CI): 1.87-2.40 by casecentred method and relative 

rate = 2.32, 95% CI: 1.85-2.91 

by SCCS]

Berger, 1998+ RCT§ Immunocompetent

adults ≥55y

Did not report VE. Reactogenicity

Any injection-site symptoms: 

Intervention: 26.5% 

Kerzner, 

2007+

RCT, USA and 

Europe

(N=762)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 28 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 35% 

Tyring, 2007+ RCT, USA, Canada, 

UK, Germany, 

Belgium

(N=698)

Immunocompetent

adults ≥55y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 42 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 62% 

Gilderman, 

2008+

RCT, USA

(N=367)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 28 days.

Reactogenicity
10

Any injection-site symptoms: 

Intervention: 46%

Leroux-Roels, 

2012+

RCT, Belgium

(n=155)

Immunocompetent

adults 50-70y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 12 months.

Reactogenicity

Redness at injection-site:

Intervention: 62% (4% were 

considered grade 3).

Vesikari, 

2013+

RCT, Finland, 

Germany, Italy, 

Spain, Netherlands

(N=759)

Immunocompetent

adults ≥70y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 28 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 46%

DiezDomingo, 

2015+

RCT, Germany and 

Spain

(N=354)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 28 days.

Reactogenicity

Intramuscular administration 

resulted in significantly fewer 

injection-site reactions 

compared to subcutaneous 

administration [47.2% vs 

69.5%, respectively]

Arnou, 2011+ Non-RCT, France

(n=96)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 28 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 52% 

(2 individuals reported severe 

injection-site reactions)

Hata, 2013+ Non-RCT, Japan

(N=20)

Immunocompetent

adults 60-70y with 

diabetes mellitus

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 1 year.

Reactogenicity

Intervention: 10%

Morrison, 

2013+

Non-RCT, USA

(N=13,681)

Immunocompetent

adults ≥64y with 

documented 

herpes zoster

Did not report VE. Serious adverse events

Rates of SAEs not significantly 

different among those with or 

without prior zoster (0.95% 
11

and 0.66%, respectively; p= 

.37)

Stanford, 

2014+

Non-RCT, USA

(N=54)

Immunocompetent

adults ≥50y

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 35 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 64% 

Yao, 2015+ Non-RCT, Taiwan

(N=150)

Adults ≥50y with 

any underlying 

chronic illness in 

stable condition

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 28 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 36% 

Choi, 2016+ Non-RCT, Korea

(N=180)

Adults ≥50y with 

any underlying 

chronic illness in 

stable condition

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 42 days.

Reactogenicity

Any injection-site symptoms: 

Intervention: 53% 

Levin, 2003+ Non-RCT, USA

(N=196)

Immunocompetent

adults ≥60y 

previously received 

VZV vaccine

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 42 days.

Reactogenicity

Pain at injection-site: 

Intervention: 48% 

Lelic, 2016+ Non-RCT, Canada

(N=240)

Nursing home 

residents, adults 

≥80y

Did not report VE. No adverse events related to 

vaccine reported within 42 

days.

Levin, 2016+ Non-RCT, USA

(N=600)

Adults ≥60y with 

any underlying 

chronic illness in 

stable condition, 

including adults 

≥70y who 

previously received 

ZVL

Did not report VE. Serious adverse events

No SAEs related to vaccine 

reported within 1 year.

Reactogenicity

Any injection-site symptoms: 

Intervention: 44% 

Baxter, 

2016b+

Non-RCT, USA

(N=376,531)

KPNC members 

who received ZVL

Did not report VE. No association found between

sudden sensorineural hearing 

loss and ZVL, OR=0.424 (95% 

CI: 0.08-1.53)
12

Willis, 2016+ Non-RCT, global Merck Adverse 

Event Reporting 

System worldwide 

postmarketing 

adverse event 

database

Did not report VE. Merck’s 10 year postmarketing analysis reviewed 

23,556 reports with a total of 

45,898 adverse events. The 

majority of reported adverse 

events were non-serious 

(93%). Most commonly 

reported adverse events were 

injection-site reactions and 

herpes zoster. There were 

some reports of PCRconfirmed VZV rash caused by 

Oka/Merck vaccine strain.

Abbreviations: ZVL: Live-attenuated zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% Confidence 

Interval; HZ: herpes zoster; PHN: post-herpetic neuralgia; SAE: Serious adverse events; RCT: randomized controlled 

trial; Non-RCT: non-randomized clinical trial; SPS: Shingles Prevention Study; STPS: Short-term Persistence Study; 

LTPS: Long-term Persistence Study; VZV: varicella zoster virus; KPNC: Kaiser Permanente Northern California; KPSC: 

Kaiser Permanente Southern California; OR: Odds ratio

*In the Shingles Prevention Study, adverse event substudy, significantly more subjects in the vaccine group had 

serious adverse events than in the placebo group (1.9% vs. 1.3%, respectively; P=0.03); A post hoc, subject-bysubject review found no clinically meaningful differences between the groups in the pathophysiology, nature, 

timing, intensity, or outcome of these events. (Oxman, NEJM, 2005)

** Ad-hoc analysis of reactogenicity among participants of the Shingles Prevention Study (Oxman, NEJM, 2005)

+ No comparison group: no participants received no vaccine or placebo. 

§ Did not report number of subjects who received ZVL

Results

GRADE of RZV studies 

Table 5. Included data, by outcome, RZV 

Outcome Number of 

subjects (number 

of studies)

Comparison 

groups

Findings

Prevention of herpes 

zoster

50-59y: 7,017 (1)

60-69y: 4,307 (1)

≥70y: 16,596 (1)

2 dose RZV

vs placebo

VE [95% CI]

• 50-59y: 96.6% [89.6-99.3]

• 60-69y: 97.4% [90.1-99.7]

• ≥70y: 91.3% [86.8-94.5]

Prevention of postherpetic neuralgia≥50y: 27,916 (1)

≥70y: 16,596 (1)

2 dose RZV

vs placebo

VE [95% CI]

• ≥50y: 91.2% [75.9-97.7]

• ≥70y: 88.8% [68.7-97.1]

Duration of protection 

against herpes zoster (up 

14,693 (1) 2 dose RZV

vs placebo

VE remained about 85% in the first 

4 years following vaccination
13

to 4 years post 

vaccination)

Serious adverse events 29,965 (8) 2 dose RZV

vs placebo

No differences in serious adverse 

events between vaccinated and 

placebo groups. No serious adverse 

events related to vaccination 

found.

Reactogenicity (Grade 3 

reaction)

10,590+ (8) 2 dose RZV

vs placebo

Grade 3 reactions more commonly 

reported in vaccinated populations 

compared to placebo. 

In phase III clinical trials (n=9,936):

• 16.5% of vaccine recipients 

reported any Grade 3 reaction 

compared to 3.1% of placebo 

recipients. 

• 9.4% of vaccine recipients 

reported Grade 3 injection-site 

reactions, compared to 0.3% of 

placebo recipients. 

• 10.8% of vaccine recipients 

reported Grade 3 systemic 

reactions, compared to 2.4% of 

placebo recipients. 

Safety and immunogenicity studies 

reported similar reactogenicity 

rates among participants receiving 

RZV

Abbreviations: y: years-old; RZV: recombinant zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% 

Confidence Interval

+

In the ZOE 50/70 Phase III clinical trials, reactogenicity data was only collected from a randomly selected sub-set 

of participants (n=9,936)

Table 6. Summary of the evidence for select outcomes with use of RZV in immunocompetent adults aged 50 

years and older 

Outcomes Design

(# studies)

Initial 

Evidence Risk of Bias Inconsistency Indirectness Imprecision Others Evidencetype

Outcome 

evidence 

type

Overall 

Evidence 

Type

Benefits

Prevent herpes 

zoster

1 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1

1

Prevent postherpetic neuralgia 1 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1
14

Duration of 

protection against 

herpes zoster (up 

to 4 years post 

vaccination)

1 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1 1

Harms

Serious adverse 

events (after any 

dose)

2 RCT 1 Not serious Not serious Not Serious Not Serious None 1

1

1

4 RCT with 

no placebo 1 Serious*(-1) Not Serious Serious‡(-1) Not Serious None 3

2 Non-RCT 2 Serious*(-1) Not Serious Serious‡(-1) Not Serious None 4

Reactogenicity 

(Grade 3 reaction)

2 RCT 1 Not serious Not serious Not Serious Not Serious None 1

1

4 RCT with 

no placebo 1 Serious*(-1) Not Serious Serious‡(-1) Not Serious None 3

2 Non-RCT 2 Serious*(-1) Not Serious Serious‡(-1) Not Serious None 4

Abbreviations: RZV: recombinant zoster vaccine; RCT: randomized controlled trial; Non-RCT: non-randomized clinical trial

*Studies were non-blinded, open-label trials ‡No placebo comparison group. Did not directly meet our policy question of comparing outcomes between vaccine and placebo recipients

GRADE of ZVL studies 

Table 7. Included data, by outcome, ZVL 

Outcome Number of 

subjects (number 

of studies)

Comparison 

groups

Findings

Prevention of 

herpes zoster

50-59y: 22,439 (1)

≥60y: ~4.7 million 

(8)

One dose ZVL vs

placebo or no 

vaccine

Vaccine efficacy against herpes zoster, 

clinical trial data: VE [95% CI]

– 50-59y: 70% [54-81]

– 60-69y: 64% [56-71]

– 70-79y: 41% [28-52]

– ≥80y: 18% [-29-48]

VE from observational studies in adults 

≥60y ranged from 33% to 51% (within 

4 years post vaccination)

Prevention of 

post-herpetic 

neuralgia

≥60y: ~4 million (8) One dose ZVL vs

placebo or no 

vaccine

Vaccine efficacy against herpes zoster, 

clinical trial data: VE [95% CI]

– 60-69y: 65.7% [20.4-86.7] 

– ≥70y: 66.8% [43.3-81.3]
15

VE from observational studies in adults 

≥60y ranged from 41% to 69% (within 

4 years post vaccination)

Duration of 

protection against 

herpes zoster (up 

to 4 years post 

vaccination)

≥60y: ~3.9 million 

(5)

One dose ZVL vs

placebo or no 

vaccine

RCT (SPS, STPS, LTPS)

VE, ≥60y, by year post vaccination:

• 1y: 62.0 [49.6–71.6]

• 2y: 48.9 [34.7–60.1]

• 3y: 46.8 [31.1–59.2]

• 4y: 44.6 [20.5–61.8]

• 5y: 43.1 [5.1–66.5]

• 6y: 30.6 [−6.0 to 54.6]

• 7y: 46.0 [28.4–60.2]

• 8y: 31.1 [11.2–47.6]

• 9y: 6.8 [−16.5 to 26.4]

• 10y: 14.1 [−11.3 to 34.9]

• 11y: −1.7 [−57.1 to 37.9]

Observational studies: ZVL wanes year 

by year. Beyond 4 years, all studies 

estimates VE ≤40% after 4 years post 

vaccination

Serious adverse 

events

≥50y: ~712,000 

(28)

One dose ZVL vs

placebo or no 

vaccine

No differences in serious adverse 

events between vaccinated and 

placebo groups in RCTs.

Overall found no serious adverse 

events associated with ZVL

In clinical trials 2 subjects with 

varicella-like rashes and zoster like 

rashes had PCR confirmed Oka/Merck 

strain varicella [54].

Reactogenicity ≥50y: ~310,000 

(25)

One dose ZVL vs

placebo

Injection-site reactions were the most 

common adverse reaction related to 

vaccination

4 studies reported moderate/severe 

(grade 3) injection-site reactions that 

ranged between 0%-4% of vaccine 

recipients

Abbreviations: y: years-old; ZVL: Live-attenuated zoster vaccine; VE: vaccine efficacy/effectiveness; 95% CI: 95% 

Confidence Interval; RCT: randomized controlled trial; SPS: Shingles Prevention Study; STPS: Short-term 

Persistence Study; LTPS: Long-term Persistence Study
16

Table 8. Summary of the evidence for select outcomes with use of ZVL in immunocompetent adults aged 50 

years and older 

Outcomes Design

(# studies)

Initial 

Evidence Risk of Bias Inconsistency Indirectness Imprecision Others Evidencetype

Outcome 

evidence 

type

Overall 

Evidence 

Type

Benefits

Prevent herpes 

zoster

2 RCT 1 Not Serious Not Serious Not Serious Not Serious None 1

1

1

7 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4

Prevent postherpetic neuralgia

1 RCT 1 Not Serious N/A Not Serious Not Serious None 1

1 2 RCT with 

limitations† 2 Not Serious Not Serious Not Serious Serious(-1) None 3

5 Obs 3 Serious**(-1) Not Serious Not Serious Not Serious None 4

Duration of 

protection against 

herpes zoster (4 or 

more years post 

vaccination)

2 RCT with 

limitations† 2 Not Serious Not Serious Not Serious Not Serious None 2

2

3 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4

Harms

Serious adverse 

events (after any 

dose)

8 RCT 1 Not serious Not serious Not Serious Not Serious None 1

1

1

13 RCT with 

limitations‡ 2 Serious‡(-1) Not Serious Not Serious Not Serious None 3

7 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4

Reactogenicity 

15 RCT 1 Not serious Not serious Not Serious Not Serious None 1

5 Non-RCT 2 Serious 1 ‡(-1) Not Serious Not Serious Not Serious None 3

5 Obs 3 Serious*(-1) Not Serious Not Serious Not Serious None 4

Abbreviations: ZVL: Live-attenuated zoster vaccine; RCT: randomized controlled trial; Non-RCT: non-randomized clinical trial; Obs: observational study

*Outcome assessors were likely aware of intervention received by participants.

**Outcome assessors were likely aware of intervention received by participants. PHN may have been underreported - PHN diagnosis based on healthcare 

encounters not self-report. †Limitations due to comparison groups. During the STPS, placebo participants could receive ZVL and censoring due to vaccination may have introduced bias 

that increased incidence of HZ among remaining placebo recipients. During the LTPS, there were no unvaccinated controls so comparison group was 

modeled. 

‡Studies were non-blinded, open-label trials with no comparison group.
17

Summary 

The evidence type for use of herpes zoster recombinant vaccine in immunocompetent adults aged 50 

years and older was determined to be type 1 (high level of evidence). The evidence type for use of the 

live attenuated herpes zoster vaccine in immunocompetent adults aged 50 years and older was 

determined to be type 1 (high level of evidence). The Advisory Committee on Immunization Practices 

reviewed the results of both GRADE analysis as well as other data demonstrating high burden of herpes 

zoster and PHN among the target population, cost effectiveness and implementation analysis. 

In October 2017, ACIP recommended:

1.) Recombinant zoster vaccine (RZV) is recommended for the prevention of herpes zoster and 

related complications for immunocompetent adults aged 50 years and older.

2.) RZV is recommended for the prevention of herpes zoster and related complications for 

immunocompetent adults who previously received ZVL.

3.) RZV is preferred over ZVL for the prevention of herpes zoster and related complications. 

These recommendations serve as a supplement to the 2008 Prevention of Herpes Zoster 

Recommendations of ACIP, for the use of ZVL in adults age 60 years and older (1,55,56).The Policy Note 

detailing the 2017 ACIP recommendations for use of herpes zoster vaccine in adults aged 50 years and 

older are available on the ACIP website.

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